The goal of the proposed research is to verify the interaction of RSK2 with the third intracellular loop of the 5-HT2A receptor that was identified in a yeast-2-hybrid screen. Once this interaction has been established, its functional significance will be determined. Our central hypothesis is that RSK2 interacts with the 5-HT2A receptor, indicating a role in signal transduction. It is likely that this interaction plays a role in the ligand-dependent activation of the MAP Kinase cascade by the 5-HT2A receptor. Inactivating mutations in the RSK2 gene are responsible for the human Coffin-Lowry syndrome. This syndrome is characterized by severe non-specific mental retardation, psychosis, and progressive skeletal deformations. The psychosis that is present in Coffin-Lowry syndrome may prove to be attributed to a disfunction of 5-HT2A signaling. To test this central idea we propose to verify the interaction of the 5-HT2A receptor's third intracellular loop and RSK2 via coimmunoprecipitation studies and through confocal microscopy studies. The binding site of RSK2 to the 5-HT2A receptor will be defined via site-directed mutageneis studies in conjunction with 2-hybrid analysis. The functional role of the interaction between RSK2 and the 5-HT2A receptor will be defined.